The ability of low levels of fluoride ions to protect teeth against the development of carious lesions is well known, although the mechanism by which the protective effect is exerted still is only poorly understood. It has been shown that fluoride can affect both the tooth enamel and the metabolism of acidogenic microorganism in plaque. Our interest has been in the latter and we have shown, in the early phase of this investigation, that low levels (1-10 ppm) of fluoride affect various strains of oral streptococci to differing degrees. It was suggested that such behavior of plaque microorganisms might explain the variability of clinical responses to water fluoridation. However, the basis for the variation in response to fluoride among the strains remained unexplained. In subsequent studies we showed that cells of Streptococcus sanguis, S. mutans, S. salivarius and S. mitis strains can accumulate fluoride against a concentration gradient. Fluoride was bound within two distinct compartments within the cells, one with a low and the other with a high affinity constant. Gel chromatographic fractionation of the cytoplasms showed that numerous macromolecular binders exist within the cells, one of which appeared to be enolase. Purified enolases from these strains, however, exhibited essentially the same responses to added fluoride. It was concluded from this that fluoride sensitivity of the intact cells is not directly related to the properties of the cellular enolases. It is expected that the information that will be gained from this study will help us to understand the basic biochemical events that give rise to the inhibition of bacterial metabolism by fluoride. This should enable us to determine why there are limitations to the clinical effectiveness of fluoride, and may lead to more effective approaches for the delivery of fluoride.